I investigated the role of C-terminal domain modifications in GluR-A mediated behavioral function using several hippocampus dependent behavioral tasks, ranging from neophobia to spatial reference memory, in a variety of genetically modified mice. Studies using GluR-A -/-knock-out (GluR-A ) mice showed that GluR-A containing AMPA receptors are required for working memory, strengthened by those findings that expression of a transgenic GluR-A -/-subunit in the forebrain of GluR-A mice partially rescues this memory deficit. In a spatial -/-reference memory task GluR-A mice learn as good as wild types. These results suggest that the GluR-A subunit is differentially involved in memory formations, and its lack in the dorsal hippocampus alters the mnemonic ability of the animals. Understanding the mechanisms by which GluR-A contributes to encoding sensory information in time, requires targeted alteration of the C-terminal domain of the GluR-A subunit. With the help of genetically engineered mice I studied three positions within the C-terminal domain, where phosphorylation of the subunit and interaction with the PDZ binding proteins take place. -/-These lines expressed either an altered or a wild type transgenic GluR-A subunit in GluR-A mice. In SA mice, the transgenetically expressed GluR-A had substitutions of serine against alanine at the phosphorylation sites S831 and S845. TG mice carried a transgene for a GluR-A subunit where the last C-terminal amino acid was deleted, which resulted in interruption of the PDZ interaction domain with the post-synaptic density proteins. The third line expressed transgenically the wild type GluR-A subunit and served as a control line. After determining the contribution of different parts of the C-terminal domain to GluR-A dependent function, I ΔFb -/- ΔFbstudied the mice lacking GluR-B (GluR-B ) or both subunits (GluR-A /B ) in hippocampal tasks. In contrast to the GluR-A deletion the GluR-B deletion was aimed to be -/- ΔFbrestricted to the forebrain. GluR-A /B mice were used to study synergistic effects of GluR-A and GluR-B deletion in the hippocampal dependent tasks. In a last group of experiments, I questioned the specificity of the hippocampal phenotypes to the AMPA receptor function using mice engineered to express Homer1a constitutively in the neocortex. The results of the studies presented in this thesis showed that hippocampal contributions to the expression of the emotional responses, emotional and motor learning as well as spatial working and reference memory are modulated by glutamatergic neurotransmission and molecular modifications of the GluR-A subunit. These findings help to identify the molecules and processes by which the hippocampus administrates its functions. 4 Molecular alterations of AMPA receptors and their effects on hippocampus dependent tasks | Verena Marx